Formulation and in vitro evaluation of cysteamine hydrochloride viscous solutions for the treatment of corneal cystinosis.

In the present study, viscous solutions of cysteamine hydrochloride (CH) were prepared by using 0.5%, 1.0%, 1.5% or 3.0% of hydroxypropylmethylcellulose (HPMC) and were evaluated for their in-vitro characteristics and stability. Osmolalities, pH and viscosity of the formulations were determined. The influence of benzalkonium chloride and autoclave sterilization on solution characteristics was also investigated. For stability assessment, the viscous solutions were stored at +4 and +25 degrees C over 12 months. In-vitro characteristics and CH contents of the stored solutions were monitored. Irritation tests for the formulations were evaluated on rabbit eyes. Dialysis sac technique was used to perform in vitro release study of the solutions containing 1.0% and 1.5% HPMC. All of the viscous solutions tested showed non-newtonian (dilatant) flow behavior. Osmolality values were ranked between 351.2+/-6.2 and 355.1+/-7.9 mOsm kg(-1), and pH values were between 3.97+/-0.1 and 3.98+/-0.2 for all the solutions. Furthermore, no significant changes in dilatant behavior, osmolality or pH values of the pure HPMC solutions were observed. After addition of the excipients or CH-excipients, increased viscosity values were noted in these formulations. Neither benzalkonium chloride nor autoclave sterilization had any influence on viscosity, pH or osmolality values of the solution containing 1.5% HPMC. Stability studies showed that a faster decrease in the concentration of CH was observed in the formulations stored at 25 degrees C compared to those kept at 4 degrees C; no changes were determined in osmolality values of the solutions at all storage conditions. Increased pH and decreased viscosity values were noted in HPMC solutions containing CH and excipients, while no changes in these values were observed for pure HPMC solutions kept at 4 and 25 degrees C. In vitro release tests revealed that 81.2% and 85.3% of CH were released from the viscous solutions containing 1.5% and 1% HPMC, respectively, in 8h. No irritation was observed when the viscous solutions were tested on rabbit and human eyes.

Treatment of malignant gliomas with mitoxantrone-loaded poly (lactide-co-glycolide) microspheres.

OBJECTIVE: Mitoxantrone (MTZ) has potent in vitro activity against malignant glioma cell lines, but it cannot be used effectively as a systemic agent for the treatment of brain tumors because of its poor central nervous system penetration. However, MTZ-loaded poly(lactide-co-glycolide) (PLGA) microspheres may be injected into the peritumoral area and into tumor tissue to provide effective and sustained local drug concentrations without causing systemic side effects. METHODS: Fisher rats were randomized into three groups. The first group (n = 9) was concomitantly implanted with rat glioma (RG2) cells and blank PLGA microspheres. The second group (n = 6) was implanted with RG2 cells and MTZ-loaded PLGA microspheres. The third group (n = 9) was implanted with RG2 cells, and MTZ-loaded PLGA microspheres were injected into the same area after 7 days. Animals were sacrificed on Day 15 or 35. Tumor volumes were measured after hematoxylin and eosin staining. Distribution kinetics of MTZ in the brain was determined by high-performance liquid chromatography in nine rats injected with MTZ-loaded microspheres. RESULTS: The tumor volumes were 76 +/- 11 and 107 +/- 11 mm (mean +/- standard error) on Days 15 (n = 6) and 35 (n = 3), respectively, in the control group. In rats treated with MTZ-loaded microspheres on Day 7, tumor volumes were significantly reduced to 17 +/- 4 and 23 +/- 2 mm on Days 15 (n = 6) and 35 (n = 3), respectively. No tumor formation was observed when glioma cells and MTZ-loaded PLGA microspheres were implanted concomitantly (n = 6). No systemic side effects or parenchymal inflammatory infiltration were observed in either group of rats. Brain MTZ concentration was highest at the injection site and declined with time and distance from the injection site and with time. CONCLUSION: These data demonstrate that MTZ-loaded PLGA microspheres can deliver therapeutic concentrations of drug to the tumor and prevent glioma growth without causing side effects. This treatment method may increase the efficiency of antineoplastic therapy and positively impact survival.

Influence of irradiation sterilization on poly(lactide-co-glycolide) microspheres containing anti-inflammatory drugs.

Gamma-irradiation is finding increasing use in the sterilization of pharmaceutical products. However, irradiation might also affect the performance of drug delivery systems. In this study, the influence of gamma-irradiation on the physicochemical properties of two commonly used non-steroidal anti-inflammatory drugs (NSAIDs) [naproxen sodium (NS) and diclofenac sodium (DS)] was investigated. The drugs were incorporated in poly(lactide-co-glycolide) (PLGA, 50:50; molecular weight 34000 or 88000 Da) microspheres. The biodegradable microspheres were irradiated at doses of 5, 15, 25 kGy using a 60Co source. Drug loading of irradiated and non-irradiated microspheres with both 34000 and 88000 Da polymers were essentially the same. A significant difference was noticed in the particle sizes of the irradiated as compared to the non-irradiated formulations. Notably, in release studies, the amount of active substance released from PLGA microspheres showed an increase with increasing irradiation dose. In DSC, the glass transition temperatures (Tg) of microspheres exhibited a slow increase with irradiation dose.